tbuckley/cabot-search huggingface dataset:
P02.09.A THE PLASTICITY AND SURVIVAL OF GLIOBLASTOMA STEM CELLS DEPEND ON GD3, WHOSE INHIBITION IS SYNERGISTIC WITH RADIO-CHEMOTHERAPY
Authors: V Hein, N Baeza-Kallee, R Berges, R Appay, E Snacel-Fazy, A Tchoghandjian, D Figarella-Branger, E TABOURET
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma is the most frequent and aggressive primary brain tumor in adults. No curative treatment is available, and the identification of relevant therapeutic targets is an unmet medical need. Our team previously demonstrated that A2B5 positive cells have a stemness behavior, with self-renewal, multipotency ability, and tumor initiation ability in vivo. A2B5 is recognizing different gangliosides, including GT3 and its precursor GD3. However, A2B5 is an IgM, that cannot be used directly as a therapeutic strategy.Then, our aim was to demonstrate that GD3 was a relevant and actionable target for glioblastoma stem cells (GSC). MATERIAL AND METHODS We used the GCS lines we already derived from fresh patient samples. Then, we sorted GD3 positive cells from patient samples to derive new GCS lines and explore GD3 properties. We downregulated the GD3 synthase (ST8Sia1) by using Sh. The tumor cells were orthotopically engrafted in nude mice. RESULTS First, we showed that GD3 was expressed by 15 to 20% of cells from patient tumor bulks but not by normal brain. Then, we showed that 60% to 90% of GSC expressed GD3. Importantly, this fraction dropped between 20 to 40% after cell differentiation. We sorted GD3 positive cells from patient samples and showed their ability to exhibit stemness properties including the generation of neurospheres (expressing stem cell markers like SOX2 and nestin), clonogenicity, and tumorigenicity after orthotopic engraftment. We also demonstrated that GD3+ cells had plasticity properties with differentiation and dedifferentiation abilities depending on their culture medium. Then, by using shST8SIA1 in GSC lines, we showed that the reduction of ST8Sia1/GD3 was associated with a decreasing size of spheres, and reduced clonogenicity and migratory capacities. Moreover, the reduction of ST8Sia1/GD3 expression increased the temozolomide and radiotherapy sensitivity in vitro with a synergistic effect. Finally, the reduction of ST8Sia1/GD3 expression in U87 cell line was associated with an increasing mouse survival after orthotopic engraftment in nude mice. CONCLUSION Taken together, our results strongly suggest that GD3 and ST8SIA1 are essential for GSC properties. GD3 appears to be an interesting and actionable stem cell marker, opening promising therapeutic development for GBM patients.
P12.07.B THE POST-SURGICAL MICROENVIRONMENT OF GLIOBLASTOMA AS THERAPEUTIC TARGET TO AVOID RECURRENCES
Authors: A TCHOGHANDJIAN
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is an incurable primary brain tumour. Most GBM patients undergo surgery prior to chemoradiation, but recurrences inevitably lead to patient death. The brain physiological regenerative responses following tumor debulking have a beneficial role in the healing process. However, they also evoke characteristic time-dependent peritumoral immune responses which can promote the formation of recurrences. The crosstalk between glial, immune and GBM cells at the surgical borders and their impact on recurrences still lacks appropriate characterization. This project aims at dissecting the GBM post-surgical microenvironment (SMe) over time and space to identify therapeutic targets and develop tailored GBM therapies to avoid the onset of recurrences. MATERIAL AND METHODS We developed a tumor resection model in transgenic mice bearing GL261 tumors and established a chronic intracranial window post-surgery by biphotonic imaging. Nuclear imaging was performed at defined time points using 99mTc-DTPA, 68Ga-RGD and 18F-FDG to evaluate neuroinflammation, neoangiogenesis, infiltrating tumor cells metabolism and BBB permeability. The dynamics of the inflammatory landscape following surgery was characterized by blood sampling and post-mortem analysis on brain samples (peripheral and local immunophenotyping by multiparametric flow cytometry; brain clearing and ultramicroscopy). RESULTS We analyzed the dynamics of recruitment and localization of immune cells coming to the resection site from the brain parenchyma or from the periphery from surgery to recurrence. BBB disruption was observed post-surgery followed by a recovery within three days. Based on the results obtained we finally tested a therapeutic approach combining the local administration of lauroyl-gemcitabine lipid nanocapsules hydrogel with the repeated systemic administration of a SMAC-mimetic drug showing an increase in survival of GBM-bearing mice. CONCLUSION This comprehensive study expands the knowledge on the SMe by analyzing the impact of BBB disruption on immune cells recruitment and the role of lymphoid and myeloid populations - as well as macrophages and microglia - on the onset of tumor recurrences. Moreover, it proposes a rationally designed combinatory treatment able to target the identified cellular targets to delay or inhibit the onset of recurrences.
P17.05.A TUMOR-TREATING FIELDS COMBINED WITH SECOND-LINE CHEMOTHERAPY REACHED PROGRESSION FREE SURVIVAL OF 8.33 MONTHS IN CHINESE RECURRENT GLIOBLASTOMA
Authors: C Guo, Q Yang, Z He, H Duan, R Liu, Y Mu
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Tumor-treating Fields (TTFields) monotherapy has been approved for recurrent glioblastoma. However, TTFields combined with second-line chemotherapy has not been well studied in China. This study aims to explore the efficacy and safety of such combination therapy for recurrent GBM. MATERIAL AND METHODS This study is a prospective, single-arm, open-label clinical trial (NCT04689087) planning to enroll 40 recurrent supratentorial GBM and use TTFields combined with physician choose second-line chemotherapy. Kaplan-Meier survival curve was used to estimate PFS, OS and survival rate. Safety of the combined treatment was assessed by AE incidence. RESULTS Thirty-four recurrent supratentorial GBM patients was enrolled from April 2019 to February 2023. The average age was 51.9 and median KPS score was 80. Seventy-seven percent (26/34) of them underwent total resection surgery and 2.9% (1/34) only experienced biopsy. Eighty-eight percent (30/34) of patients started TTFields when they were first diagnosed as recurrence, while 12% (4/34) patients started TTFields at their second time recurrence or latter, and average compliance of TTFields was 85.5%. As for molecular biomarkers, 47.1% (16/34) patients were MGMT methylated and 38.2% (13/34) were TERT mutant. Since the study initiated in 2019, one IDH-mutant patients were also enrolled. Second-line chemotherapy was combined with antiangiogenic therapy in 47.1% (16/34) patients. The median follow-up period was 8.33 months. Median PFS of these 34 recurrent GBM patients was 8.33(95% CI 4.72-11.95) months, but median OS was not reached. Six months PFS rate was 56.8% (EF-11 historical data of physicians choose chemotherapy was 15.1%) and 6 months OS rate was 74.8%. Two thirds of patients experienced grade 1 or 2 skin adverse events which can be relieved by topical corticosteroids. CONCLUSION TTFields combined with second-line chemotherapy showed favorable efficacy and safety in Chinese recurrent GBM patients.
P10.08.B PI3K INHIBITION FOR SENSITIZING CANCER CELLS TO TUMOR TREATING FIELDS (TTFIELDS)
Authors: A Klein-Goldberg, T Voloshin, E Zemer-Tov, R Paz, L Somri-Gannam, A Volodin, L Koren, K Wainer-Katsir, A Haber, E Dor-On, M Giladi, U Weinberg, Y Palti
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Tumor Treating Fields (TTFields) are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cell death. TTFields therapy is approved for treatment of adult patients with glioblastoma (GBM) or unresectable pleural mesothelioma. Clinical trials are underway in other solid tumors, including ovarian cancer and non-small cell lung carcinoma (NSCLC). The objective of this study is to identify possible mechanisms involved in reduced sensitivity of cancer cell to TTFields, and explore strategies to circumvent them. MATERIAL AND METHODS GBM U-87 MG, ovarian cancer A2780, and NSCLC H1299 cells were treated with continuous long-term application of TTFields (1.7 V/cm RMS, 200 or 150 kHz, 6 or 13 days, specific conditions depending on cell line). Changes in signaling pathways were examined for cells following 3 days of treatment with Luminex multiplex assay, followed by Western blot validation for specific pathway markers. In vivo validation was performed in ovarian cancer (MOSE-L), hepatocellular carcinoma (N1-S1), and NSCLC (LL/2) tumor sections from animals treated with TTFields utilizing immunohistochemistry. Next, efficacy of TTFields concomitant with relevant inhibitors was evaluated in vitro and in mice inoculated orthotopically with ovarian cancer cells (MOSE-L). Tumor volume was measured at study end by luciferin signal detection using the In Vivo Imaging System (IVIS). RESULTS TTFields inflicted a cytotoxic effect on the cancer cells that increased over time, though with moderately reduced sensitivity following prolonged treatment application. PI3K/AKT signaling pathway was shown to be activated in treated cells, with the amplitude of AKT phosphorylation increasing over time. AKT phosphorylation was also demonstrated in tumor sections of animals treated with TTFields. Experiments performed with concomitant PI3K/AKT pathway inhibitors sensitized the cells to TTFields, enhancing cytotoxicity in vitro and treatment efficacy in vivo. CONCLUSION PI3K/AKT signaling pathway is involved in cancer cell reduced sensitivity to TTFields, and inhibition of this pathway sensitizes cancer cells to TTFields.
P07.05.B DNA-METHYLATION PROFILING IS AN EFFECTIVE ASSET FOR IDENTIFICATION OF TUMORS IN SUSPECTED, YET IMMUNOHISTOCHEMICALLY UNSPECIFIABLE, NEURO-ONCOLOGICAL CASES
Authors: J S Onken
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Patients with a suspected neurooncological disease on radiographic images and no histopathological evidence of a tumor on the surgically retrieved tissue, pose a great challenge for clinicians and neuropathologists. DNA methylation-based classifications and copy number variation (CNV) analysis allow robust brain tumor classification. Here, we aim to evaluate their diagnostic properties in histopathologically unspecifiable or negative cases. MATERIAL AND METHODS We screened all neurosurgical cases, which underwent surgery at our institution between 2009 and 2021, with suspected neurooncological, but negative or unspecific histopathological diagnosis. We differentiated two groups: cases with cell-enriched, reactive tissue (+/- single tumor cells), insufficient to fully classify the lesion according to criteria of WHO for CNS tumors (group 1) and cases without histological evidence of tumor cells (group 2). In both groups, DNA methylation profiling was applied. Endpoints were diagnostic results of DNA methylation profiling (classifier Score ≥0.9) and evidence/no evidence of tumorigenic CNV alterations and eventually feasibility to make a diagnosis according to WHO 2021 criteria for brain tumors. RESULTS 23 cases with unspecifiable histopathological diagnosis were identified, out of whom 5 (21.7%) were confirmed as healthy brain tissue via DNA-methylation profiling, whereas the eventual diagnosis of tumorigenic tissue was provided in 18 (78.3%) cases. 14 of these were assigned to group 1, 4 cases to group 2. In 6 cases of group 1 (42.9%) DNA-methylation profiling resulted in a successful tumor classification (score ≥0.9) compared to 1 case (25%) in group 2. CNV indicated tumorigenic alterations in 9 (64.3%) patients in group 1 and 2 (50%) patients in group 2. Specific tumor alterations in the CNV were found in 8 (57.1%) patients in group 1 and in 1 (25%) patient in group 2. Combining CNV and DNA-methylation profiling, a final tumor diagnosis according to WHO 2021 criteria was feasible in 9 (64.3%) cases in group 1 and 3 (75%) cases in group 2. Median time from surgery to histopathological diagnosis was 6 and 7 days and 32.5 and 31 days for integrated diagnosis (group 1 vs. group 2). CONCLUSION Molecular diagnostics with DNA-methylation profiling and CNV analysis substantially increases the likelihood of a definitive diagnosis according to 2021 WHO criteria for these challenging cases.
JS03.7.A INTERPLAY BETWEEN SELF-REPORTED AND PERFORMANCE-BASED SYMPTOMS IN PATIENTS WITH GLIOMA AND MENINGIOMA - A NETWORK ANALYSIS AND COMPARISON BETWEEN DIAGNOSES
Authors: E Butterbrod, M van de Glind, G Rutten, M Sitskoorn, K Gehring
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Patients with brain tumors show complex symptomatology often involving self-reported complaints, e.g., concerning self-perceived cognitive function (SCF), fatigue or mood, as well as deficits in cognitive performance. Understanding the interplay between symptoms across diagnoses is crucial for intervention, but remains challenging. This study used network analysis to 1) uncover unique relationships between various multidimensional self-reported symptoms and cognitive performances in patients with meningioma and glioma, and 2) investigate differences in symptom networks between diagnoses. MATERIAL AND METHODS We used pre-surgical data from patients with meningioma (n=240) and glioma (n=208). Two Gaussian graphical models were constructed to explore conditional relationships among symptoms in the two samples. Included as symptoms in the networks were ten patient-reported measures: SCF (3 nodes), Anxiety, Depression, and Fatigue (5 nodes), and 5 cognitive performance measures: Inhibition, Cognitive flexibility, Verbal memory, Processing speed and Psychomotor speed. We evaluated the importance of the symptoms with three centrality indices; node strength, betweenness and closeness. We compared features of the networks between the diagnoses with a Network Comparison Test. RESULTS In both samples, particularly strong connections existed between Anxiety and Depression, Forgetfulness and False Triggering (SCF nodes), and General Fatigue and Physical Fatigue. These positive relationships were significantly stronger than most of the other relationships. The most central symptoms, based on the strength of their connections with other symptoms, were Forgetfulness, General Fatigue and Inhibition in glioma patients, and Forgetfulness, Physical Fatigue and Depression in meningioma patients. Activity-related fatigue appeared as the least central symptom in the glioma network, but it was in the top 5 in the meningioma network. The difference in the number of relationships found (meningioma: 49 vs. glioma: 41), was not significant. Visual inspection of the networks suggested additional connections between multiple fatigue and cognition nodes in meningioma that were absent in glioma. Significant differences were found between the networks regarding strength of the relationships General Fatigue-Physical Fatigue (stronger in glioma), and Physical Fatigue-Activity-related Fatigue (stronger in meningioma), p’s &amp;lt; .01. CONCLUSION While symptom networks of patients with glioma and meningioma show similarities, they appear to differ with regard to which symptoms play a more central role and how strongly some symptoms are related. Particularly fatigue subtypes may carry different importance. Information that multidimensional symptom networks provide about how symptoms interact can guide treatment decisions for patients with different diagnoses.
P15.01.A FET PET SENSITIVITY IN PRIMARY BRAIN TUMORS ACCORDING TO CNS WHO 2021: VALUE AND PITFALLS IN PRESURGICAL IMPLEMENTATION
Authors: C Oster, T Blau, K Keyvani, T Schmidt, L Lazaridis, U Sure, C Kleinschnitz, B Scheffler, K Herrmann, F Barbato, S Kebir, M Glas
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND FET PET imaging has emerged as a valuable tool in the characterization of unclear brain lesions that cannot be clearly diagnosed with conventional diagnostic METHODS .In 2021,the Central Nervous System(CNS) World Health Organization(WHO) introduced significant changes in the classification of CNS tumors.Notably,under the new classification,certain cases of glioma may be reclassified as glioblastoma.Unfortunately,a subset of gliomas,as defined by the 2016 WHO classification,may exhibit no detectable FET uptake and lack contrast enhancement on MRI,which can lead to underestimation of such tumors and potentially result in inappropriate treatment decisions. MATERIAL AND METHODS In this study,we conducted a retrospective analysis of all patients who underwent FET PET imaging of the brain between 2017 and 2021,prior to their first surgical brain intervention.We obtained the results from presurgical MRI scans and categorized the lesions based on whether they exhibited contrast media enhancement or not,in addition to the postsurgical histopathologic diagnosis.Our analysis focused on identifying the number of cases in which the diagnosis of malignancy was underestimated in the context of the WHO 2016 classification.To further investigate these cases,we conducted NGS and 850k-analysis to reclassify the results in accordance with the new classification.Finally,we assessed the number of cases that were underestimated using the new classification criteria. RESULTS After enrolling 85 patients,our study found that according to the 2016 classification,preoperative imaging underestimated malignancy in 14 cases (16%) where histopathological analysis revealed high-grade malignant brain tumors.In 32 cases (27%), the preoperative imaging correctly suggested a malignant tumor,which was later confirmed by histopathological analysis after surgery.Additionally,22 cases were suggested to be low grade or benign,which was confirmed by postsurgical tissue analysis. Further analysis revealed that some patients diagnosed with low-grade glioma according to the WHO 2016 classification actually had molecular glioblastomas after reclassification.The final results of this reclassification after the CNS WHO 2021 will be presented at the annual meeting. CONCLUSION The findings of this study suggest that presurgical brain imaging,as per the WHO 2016 classification,may underestimate the malignancy of unclear brain lesions in up to 16% of cases.Our initial analysis also indicates that this underestimation may be more prevalent when using the new WHO CNS classification from 2021.Therefore,caution is advised when recommending non-surgical follow-ups in such cases, as it may lead to incorrect treatment decisions and worse patient outcomes.
OS10.5.A PERIVASCULAR CONTAINED T CELLS IN IDH-MUTANT ASTROCYTOMA CO-LOCALIZE WITH GEMISTOCYTIC TUMOR CELLS OF AN ASTROCYTE-STATE AND MACROPHAGES WITH AN IMMUNE-STIMULATORY PHENOTYPE
Authors: L van Hijfte, M Geurts, I de Heer, W R Vallentgoed, H E Balcioglu, R Debets, P French
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Isocitrate dehydrogenase mutant (IDHmt) astrocytoma is considered a T cell excluded tumor, yet little is known regarding the underlying cues that may drive T cell exclusion. To aid better understanding of this mechanism in IDHmt astrocytoma, we systematically characterized the immune microenvironment of this tumor type. METHODS We performed and analyzed multiplex immunofluorescence stainings for lymphocytes, myeloid cells and IDH1-R132H of 1293 regions from 75 IDHmt astrocytomas. We consequently performed bulk, single nucleus and spatial RNA sequencing of samples from the same cohort. Integrative analysis of data from these platforms allowed for the identification of unique tumor and immune cell subsets that are crucial in the spatial organization of the immune microenvironment and T cell containment in IDHmt astrocytoma. RESULTS IDHmt astrocytoma showed three spatially distinct distribution patterns of T cells: regions with perivascular accumulation of T cells, regions with T cells in the tumor stroma and T cell absent regions. Perivascular accumulation of T cells, known as T-cell cuffs, was the most abundant pattern in our data. Spatially, there was a significant increase of tumor cells around T cell cuffs that showed a gemistocytic phenotype, a tumor cell type that is histologically characterized by a large eosinophilic cytoplasm and ectopically localized nucleus. Gemistocyte-high tumors (&amp;gt; 20% of all tumor cells) demonstrated enhanced expression of genes related to immune cell migration and activation that were reliably expressed by tumor associated macrophages and T cells. Notably, gemistocytic tumor cells were identified as a distinct sub-cluster of the ‘astrocyte-like’ transcriptomic cell state with a phenotype that is linked to astrogliosis and expressed CD44, TNC and TGFB2. Moreover, gemistocytic tumor cells were spatially associated with a CD83+ subpopulation of tumor-associated macrophages that resemble reactive microglia in astrogliosis and show increased expression of the chemo-attractants CCL3, CCL4 and CCL4L2. CONCLUSION Using different modalities for spatial and single cell profiling of RNA and protein, we uncovered a previously unknown relationship between the immune system and tumor cells in IDHmt astrocytoma. We found that gemistocytic tumor cells showing an ‘astrocyte-like’ state co-occur with perivascular contained T cells and immune-stimulatory macrophages in IDHmt astrocytomas. The transcriptional profiles of these tumor cell subsets and macrophages point towards a CNS specific defense mechanism of glial cells associated with T cell exclusion.
P10.04.B LONGITUDINAL [18F ]FET-PET-BASED IMAGING AND PROFILING OF PDGFB-DRIVEN EXPERIMENTAL GLIOMA USING THE RCAS-TVA SYSTEM
Authors: H Becker, S Castaneda-Vega, K Patzwaldt, J M Przystal, B Walter, F C Michelotti, D Canjuga, M Tatagiba, B Pichler, S C Beck, E C Holland, C la Fougère, G Tabatabai
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma are aggressive and incurable primary tumors of the central nervous system. As patients present with already established tumors, longitudinal imaging by MRI and [18F]FET-PET in human glioblastoma for characterizing temporal and spatial metabolic alterations is only possible to characterize alterations during therapy, but not during tumor evolution. In this regard, genetically engineered preclinical models are very relevant. The replication-competent avian sarcoma-leukosis virus (RCAS)/tumor virus receptor-A (tva) system provides a high grade of spatial and temporal control of somatic gene delivery in vivo. In this study, we used longitudinal MRI and [18F]FET-PET to characterize the evolution and growth of platelet-derived growth factor B (PDGFB)-driven glioma model using the RCAS-tva system. MATERIAL AND METHODS DF-1 cells transfected with PDGFB were implanted into adult 129S.Tg(NES-TVA)-Cdkn2a−/− mice intracranially. Mice received MRI twice and [18F]FET-PET measurements once per week. Longitudinal growth pattern and [18F]FET-PET uptake were assessed and analyzed. We measured symptom-free survival and performed immunohistochemistry on collected tumor tissue samples. RESULTS We observed robust tumor formation with highly reproducible symptom-free survival times of treatment-naïve experimental animals. Contrast-enhanced MRI volumetry revealed exponential growth dynamics starting around day 25 after DF-1 inoculation. Here, the PDGFB-driven gliomas present an escalating [18F]FET-PET uptake as well as increasing BBB permeability over time. These imaging features match the clinical scenario, which underlines the translational relevance of this model. Histology corroborated the imaging findings and an immunogenic glioma-associated microenvironment. CONCLUSION These data provide further valuable insights into this RCAS/tva-based PDGFB-driven murine glioma model and advocates for an imaging-stratified design of preclinical therapeutic interventions.